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Atracurium besylate

[1]

is a neuromuscular-blocking drug or skeletal muscle relaxant in the category of non-

depolarizing neuromuscular-blocking drugs, used adjunctively in anesthesia to facilitate endotracheal intubation and to provide skeletal muscle relaxation during surgery or mechanical ventilation. Atracurium is classified as an intermediate-duration non-depolarizing neuromuscular-blocking agent.

History[edit]
Atracurium besylate was first synthesized in 1974 by George H. Dewar, a pharmacist and a medicinal chemistry doctoral candidate in John B. Stenlake's medicinal chemistry research group in the Department [2] of Pharmacy at Strathclyde University, Scotland. Dewar first named this compound "33A74" before its eventual emergence in the clinic as atracurium. Atracurium was the culmination of a rational approach to drug design to produce the first non-depolarizing non-steroidal skeletal muscle relaxant that undergoes chemodegradation in vivo. [3] The term chemodegradation was coined by Roger D. Waigh, PhD, also a pharmacist and a postdoctoral researcher in Stenlake's research group. Atracurium was licensed by Strathclyde University to The Wellcome Foundation [4] Ltd. UK, which developed the drug (then known as BW 33A ) and its introduction to first human trials in [5][6] [7] 1979, and then eventually to its first introduction (as a mixture of all ten stereoisomers ) into clinical anesthetic practice in the UK, in 1983, under the tradename of Tracrium. The premise to the design of atracurium and several of its congeners stemmed from the knowledge that a bisquaternary structure is essential forneuromuscular-blocking activity: ideally, therefore, a chemical entity devoid of this bis-quaternary structure via susceptibility to inactive breakdown products by enzymic-independent processes would prove to be invaluable in the clinical use of a drug with a predictable onset and duration of action. Hofmann elimination provided precisely this basis: It is a chemical process in which a suitably activated quaternary ammonium [8] compound can be degraded by the mildly alkaline conditions present at physiological pH and temperature. In effect, Hofmann elimination is a retro-Michael addition chemical process. It is important to note here that the physiological process of Hofmann elimination differs from the non-physiological Hofmanndegradation process: the latter is a chemical reaction in which a quaternary ammonium hydoxide solid salt is heated to 100 °C, or an aqueous solution of the salt is boiled. Regardless of which Hofmann process is referenced, the end-products in both situations will be the same: an alkene and a tertiary amine. The approach to utilizing Hofmann elimination as a means to promoting biodegradation had its roots in much earlier observations that the quaternaryalkaloid petaline (obtained from the Lebanese plant Leontice leontopetalum) readily underwent facile Hofmann elimination to a tertiary amine calledleonticine upon passage through a basic (as opposed [9] to an acidic) ion-exchange resin. Stenlake's research group advanced this concept by systematically synthesizing [10][11][12][13] [14] numerous quaternary ammonium β-aminoesters and β-aminoketones and evaluated them for skeletal [5][12] [2][15] muscle relaxant activity: one of these compounds, initially labelled as 33A74, eventually led to further clinical development, and came to be known as atracurium. Atracurium's limited clinical utility for the future was presaged with the marketing approval of cisatracurium in 1995 under the tradename of Nimbex. Cisatracurium is the R-cis R-cis isomer component of the ten stereoisomers that [7] comprise atracurium. The pharmacodynamic and adverse effects profile of cisatracurium proved to be superior to that of atracurium, which rapidly led to decline in the use of atracurium. The clinical development of cisatracurium was undertaken by Burroughs Wellcome Co. (and its parent The Wellcome Foundation Ltd.), from 1992 to 1994, and by the time of its approval for use in humans by the US Food and Drug Administration, Burroughs Wellcome Co. had merged with Glaxo Inc., and Nimbex was subsequently marketed worldwide byGlaxoWellcome Inc.
[2]

Neuromuscular function parameters: definitions[edit]

ED95: the dose of any given neuromuscular-blocking agent required to produce 95% suppression of muscle twitch (e.g., the adductor pollicis) response with balanced anesthesia

A C radiolabeled metabolism study in cats confirmed the lack of hepatic or renal involvement in the metabolism of atracurium: radioactivity eliminated in bile and urine was predominantly from metabolites rather than the unchanged parent [17] drug. 25%-75% recovery index: an indicator of the rate of skeletal muscle recovery .v. Laudanosine.) would be of no pharmacological importance.6 mg kg-1 i. equal depression in depolarising and fading response with nondepolarising blocker. dogs and rhesus monkeys. defined as follows: Classification of neuromuscular-blocking agents by duration of pharmacological action (minutes) Parameter Ultra-short Duration Short Duration Intermediate Duration Long Duration Clinical Duration (Time from injection to T25% recovery) 6-8 12-20 30-45 >60 Recovery Time (Time from injection to T95% recovery) Recovery Index (T25%-T75% recovery slope) <15 25-30 50-70 90-180 2-3 6 10-15 >30 Preclinical pharmacology[edit] Several publications describe the preclinical pharmacology of atracurium.provides a measure of the full recovery of neuromuscular function     Duration of action: definitions[edit] Neuromuscular-blocking agents can be classified in accordance to their duration of pharmacological action. However.5 –4 mg kg-1.provides a measure of the recovery of neuromuscular function T4:T1 ≥ 0. the quaternary acid and metholaudanosine were devoid of neuromuscular blocking activity within the dose range 0. and quite likely that the quantities present either as an impurity or formed after administration of therapeutic doses of atracurium (0.essentially. Hughes and Payne described the [16] 14 preliminary pharmacology of atracurium in anesthethetized cats.7: a 70% ratio of the fourth twitch to the first twitch in a TOF . They concluded that the metabolites were of low potencies.3–0. Clinical duration: difference in time between time of injection and time to 25% recovery from neuromuscular block Train-of-Four (TOF) response: stimulated muscle twitch response in trains of four when stimuli are applied in a burst of four as opposed to a single stimulus. [18] .9: a 90% ratio of the fourth twitch to the first twitch in a TOF . the difference in time between the time to recovery to 25% and time to recovery to 75% of baseline value T4:T1 ≥ 0. Chapple and Clarke reported on the neuromuscular and cardiovascular effects of the breakdown products of atracurium and related substances in anesthetized cats.

Otherwise. There are three cis-cis isomers (an enantiomeric pair and a meso structure). the quaternary alcohol. Hofmann elimination is a temperature. or by the status of renal or hepatic [28] function. Most commonly. age.and pH-dependent process.hypotension. which could give 16 structures. and the monoquaternary analogue. hypotension and a consequent [citation needed] reflextachycardia. atracurium itself is [23][26] dependent on hepatic and renal functions that tend to be less efficient in the elderly population. 2′R at the four stereocentres. is associated [29] with histamine release upon rapid administration of a bolus intravenous injection. there is a plane of symmetry running through the centre of the diester bridge. Unsourced material may be challenged and removed. The initial in vitro studies appeared to indicate a major role for ester hydrolysis but. cisatracurium (Nimbex) is one such agent that does not elicit histamine release even up to [citation needed] 5xED95 doses. and therefore atracurium's rate of degradation in vivo is highly influenced by body pH and temperature: An increase in body pH favors the elimination [6][16] [21] process. and trans−trans isomers are in the ratio of 10. There are some exceptions to this rule. and. the breakdown process is [22] [23] [24][25][26][27] unaffected by the level of plasma esterase activity. [cis-cis isomers ≈ 58% cis-trans isomers ≈ 36% trans-trans isomers ≈ 6%]. and so 6 meso structures (structures that can be superimposed by having the opposite configuration then 180° rotation) are formed. there is no reason to administer adjunctive . Clinical pharmacology[edit] Atracurium is susceptible to degradation by Hofmann elimination and ester hydrolysis as components of the in [19][20] [19] vivo metabolic processes. obesity.within this dose range. 1′R. Although there are four stereocentres. 2R. with increasing doses administered at the same rate. laudanosine. This reduces the number from sixteen to ten. while the facial flush may take around 3–4 [citation needed] minutes to dissipate. metholaudanosine and the monoquaternary analogue at 4 mg kg1 doses resulted in a significant reduction in mean arterial pressure (by 30 –70 mm Hg). laudanosine. e.. it has the configuration 1R. the histamine release following administration of these agents is associated with observable cutaneous flushing (facial face and arms. excretion of the metabolite. The pharmaceutical presentation is a mixture of all ten possible stereoisomers. with accumulation of clinical data over time. commonly). One of the three cis-cis structures is marketed as a single-isomer preparation. the quaternary acid. (August 2012) The tetrahydroisoquinolinium class of neuromuscular blocking agents. cis−trans. whereas a decrease in temperature slows down the process. On the other hand. whereas significant vagal blockade occurred after 4 mg kg-1 of the quaternary monoacrylate. the quaternary alcohol. reflex tachycardia and cutaneous flush [edit] This section needs additional citations for verification. The liberation of histamine is a dose-dependent phenomenon such that. Administration of the quaternary monoacrylate. in general. Because these effects are so transient. the preponderence of evidence indicated that Hofmann elimination at [20] physiological pH is the major degradation pathway vindicating the premise for the design of atracurium to undergo [21] an organ-independent metabolism. four cis-trans isomers (two enantiomeric pairs). there is a greater propensity for eliciting histamine release and its ensuing [citation needed] sequelae. Please help improve this article by adding citations to reliable sources. Significant sympathetic blockade after preganglionic nerve stimulation was observed only with the monoquaternary analogue at a dose of 4 mg kg-1. It should be noted though that these sequelae are very transient effects: The total duration of the cardiovascular effects is no more than one to two minutes. the quaternary alcohol and the monoquaternary analogue produced a dose-dependent neuromuscular block.g. to a small extent.5 :6. The beta-blocking drug Nebivolol has ten similar structures with 4 stereocentres and a plane of symmetry.2 :1. but only two are presented in the pharmaceutical preparation. cisatracurium (trade name Nimbex). they reported that the quaternary monoacrylate. The proportions of cis−cis. Adverse effects[edit] Histamine release . and three trans-trans isomers (an enantiomeric pair and a meso structure).

were evident only at plasma concentrations 8 to 10 times greater than those observed in . this particular undesirable effect does not appear to be observed nearly as often as that seen with rapacuronium. the marketing focus was single-mindedly to regurgitate and emphasize that the tetrahydroisoquinolinium class elicited histamine release that could prove to be a danger to the cardiovascular stability of the patient during surgical procedures. 2001 from clinical use (<2 years after its approval by the US [35] FDA on August 18. pancuronium. However. and. which had to be [34] withdrawn voluntarily during the week of March 19. There was complete failure to disseminate the true picture that not only are these effects transient but that the extent of the hypotensive effect and the reflex tachycardia are rarely of clinical significance and therefore did not require adjunctive therapy. as well as [47] [48][49] [50][51] [52] alcuronium. Indeed.a steroidal neuromuscular-blocking agent marketed by Organon. as a consequence. now subsumed into GlaxoSmithKline) and vecuronium (Norcuron . [30][31][32][33] Laudanosine – Epileptic foci[edit] Because atracurium undergoes Hofmann elimination as a primary route of chemodegradation. following its administration. That is not to say that bronchospasm was an unknown phenomenon prior to rapacuronium: Occasional reports of bronchospasm have been [39][40][41] [42][43][44][45][46] noted also with the prototypical agents.see NME Drug and New Biologic Approvals in 1999) after several serious events [36][37] [38] ofbronchospasm. fact and information pertaining to adverse events were distorted to suit taste.rapacuronium (Raplon . in the fierce battle to win market share for sales of the "steroidal" versus the terahydroisoquinolinium class of neuromuscular-blocking agents. both for the public and for atracurium. 1999 . one of the major metabolites from this process is laudanosine. and. a cat study modelling anephric patients went so far as to corroborate that EEG changes. instead.the posited hypothesis being that the laudanosine produced from the chemodegradation of parent atracurium would cross the [55] blood–brain barrier in sufficiently high enough concentrations that lead to epileptogenic foci. The most common misinformation seeded into the minds of anesthesiologists was the failure to categorically state that the cardiovascular effects following histamine release were transient. Fortunately. as evidenced by the complete lack of any clinical literature advocating the need for adjunctive antihistamine use concomitantly with the administration of tetrahydroisoquinolinium neuromuscular-blocking agents. Inc. now subsumed into Merck & Co. now subsumed into Merck & Co. when observed. much misinformation was deliberately disseminated regarding histamine release and its effects: this was particularly so in the 1980s and 1990s shortly after the near simultaneous competitive clinical introduction of atracurium (Tracrium a bistetrahydroisoquinolinium neuromuscular-blocking agent marketed by Burroughs Wellcome Co. erroneous information was quickly and subtly disseminated very shortly after the clinical introduction of atracurium that the clinical use of atracurium was likely to result in a terrible tragedy because of [53] the significant clinical hazard by way of frank seizures induced by the laudanosine by-product . including five "unexplained" fatalities. Inc.therapy to ameliorate either the cutaneousor the cardiovascular effects. rapid initial investigations irrefutably failed to find any overt or EEG evidence for a [56][57] connection between atracurium administration and epileptogenic activity. tubocurarine and succinylcholine.). which led to the latter's withdrawal of approval for clinical use worldwide.). Inc. However. and gallamine. these ill-willed beguiling notions have persisted through the decades and become ingrained with each successive generation of newly qualified anesthesiologists and CRNAs (certified registered nurse anesthetists) to the extent that the mere mention of "benzylisoquinolines" (the erroneous but commonly used class name for tetrahydroisoquinolinium neuromuscularblocking agents) immediately conjures images ofhistamine release and generates serious anxiety. because laudanosine is cleared primarily via renal excretion.. vecuronium. The issue of bronchospasm acquired considerable prominence in the neuromuscular-blocking agents arena after the spectacular failure of a clinically introduced neuromuscular-blocking agent. a tertiary amino alkaloid reported to be a modest CNS stimulant with [53] [54] epileptogenic activity and cardiovascular effects such a hypotension and bradycardia.a steroidal neuromuscular-blocking agent marketed by Organon. As part of the then fierce marketing battle between the competing pharmaceutical companies (Burroughs Wellcome Co.Pulmonary compliance[edit] Bronchospasm has been reported on occasion with the use of atracurium. Bronchospasm . and Organon. Thus.) with their respective products.

undergoes chemodegradation via Hofmann elimination in vivo. Laudanosine is also a metabolite of cisatracurium that. Thus. when introduced directly into the CNS. in fact. work by Cardone et al. there is now little doubt that laudanosine accumulation and related toxicity will likely ever be seen with the [54] doses of atracurium that are administered in clinical practice.humans during infusions of atracurium. laudanosine accumulation and related CNS or cardiovascular toxicity were unlikely . Furthermore. confirmed that. the cat study predicted that. almost a decade later. it is the steroidal neuromuscular-blocking agents pancuronium and vecuronium that. [58] .a prediction that correlated very well with a study in patients with renal failure and undergoing cadaveric renal [59] [60] transplantation. because of its identical structure to atracurium. Plasma concentrations of laudanosine generated are lower when [54] cisatracurium is used. Just over two decades later with uninterrupted clinical availability of atracurium. Unlike the two steroidal agents. neither atracurium nor laudanosine caused such accumulation of intracellular calcium. were likely to cause acute excitement and seizures. owing to accumulation of cytosolic calcium caused by activation of acetylcholine receptor ion channels.. following atracurium administration in an anephric patient.